Preparation of substituted bisaminophenyl ethylene glycols



Patented Aug. 14, 1951 PREPARATION OF SUBSTITUTED BIS- AMINOPHENYL ETHYLENE GLYCOLS Milton J. Allen, Baltimore, Md., assignor to .the United States of America as represented by the AdministratonFederal Security Agency No Drawing. Application November 5, 1948, Serial No. 58,630

4 Claims. (c1. 204 'm (Granted under the act of March 3, 1883, as amended April 30, 1928; 370 0. G. 757) The invention described herein may be manufactured and used by or for the Government of the United States for governmental purposes without the payment to me of any royalty thereon in accordance with the provisions of the act of April 30, 1928 (ch. 460, 45 stat. L. 467).

This invention relates to the production of pinacols, and, more particularly, relates to the production of pinacols by electrolytic bimolecular reduction. Still more particularly, this invention relates to the production of a,B-SllbStltllt8d bisaminophenyl ethylene glycols by the electrolytic bimolecular reduction of compounds containing the aminophenyl ketone nucleus.

Accordingly, this invention has for an object the production of aminoaryl pinacols by the electrolytic bimolecular reduction of aminophenyl ketone compounds. Another object of this invention is to provide electrolytic reduction conditions for the production of 0.,BSllbt1tllt8d bisaminophenyl ethylene glycols in a very high yield. Still another object of this invention is to provide a process for the preparation of new compounds having anti-estrogenic properties. Another object is the preparation of compounds used as intermediates in the preparation of therapeutically active compounds.

The foregoing and other objects hereinafter apparent are accomplished in accordance with this invention wherein bis-aminophenyl pinacols are produced by subjecting a solution of a compound containing the aminophenyl ketone nucleus to electrolytic reduction. In one preferred embodiment, para-amino acetophenone is sub jected, in a hydrochloric acid solution, to electrolytic reduction at a temperature not higher than 40 C. and at a substantially constant overvoltage above the decomposition potential of para-amino acetophenone but below the overvoltage at which substantial quantities of molecular hydrogen are liberated.

While it is not intended to limit this invention by any theory of operation, it is thought that the following chemical equation expresses the course of the reaction:

0 g 2H 2H2N -R electrolytic reduction In the equation, B. may be alkyl, aryl or the like. Inthe acidic solution employed. the pinacol 2 is first secured in the form of a salt with the selected acid, for example, hydrochloric acid yields the hydrochloride salt. After formation of the pinacol dihydrochloride by electrolytic reduction, the free base is liberated by neutralization.

Suitable compounds for pinacol formation in accordance with this invention include compounds containing the aminophenyl ketone nucleus, such as, for example, the ortho, meta and para amino acetcphenones, propiophenones, butyrophenones, and other amino arylalkyl ketones, as well as the amino diaryl ketones such as, for example, bis-(aminophenyl) ketones and similar diaryl ketones. Preferably, para-aminoacetophenone is employed for electrolytic bimolecular reduction in accordance with this invention since there results a very high yield of the corresponding pinacol.

The electrolytic production of pinacols in accordance with this invention is preferably carried out in an acidic solution, whereby transmission of the electric current and solubility of the selected aminophenyl ketone are both promoted. Acidic substances capable of conductin electric current readily may be used, such as, for example, sulfuric acid, acetic acid, formic acid, and preferably hydrochloric acid. Mixtures of acids or acids and ionizable salts may be employed.

In carrying out the electrolytic bimolecular re duction to form a pinacol, it has been found that the employment of a diaphragm type electrolytic cell is preferable, inasmuch as the blmoleoular reduction takes place in solution adjacent the cathode and it is desirable to minimize physical contact of the reduced compound with the anod to prevent reoxidation of the product. Any suitable semi-porous or semi-permeable membrane can be employed to provide a diaphragm such as, for example, sintered glass, porous porcelain, and

. preferably, a regenerated cellulose foil, such as that sold to the trade under the name of Visking (normally employed as a sausage-casing material). Obviously, in the electrolytic reduction, the anode is surrounded with diluted acid at the commencement of the reaction and the acidic solution of the aminophenyl ketone is placed in the cathode chamber. A mercury cathbe carried out at a substantially constant overvoltage above the decomposition potential of the compound being reduced but below the overvoltage at which substantial quantities of molecular hydrogen are liberated. It has been found that an overvoltage of from 1.2 to 1.6 volts may be employed and preferably, the overvoltage is main--- tained at about 1.5 volts for para-amino acetophenone. Other selected keto-aniline compounds require an overvoltage as high as 2 volts or higher. In general, it hasbeen found that an applied voltage between 4 and 7 volts provides the desired overvoltage, taking into consideration the cell resistance and other electrolysis factors. At an overvoltage which is too low, pinacol formation is repressed and the yields are low, while at a high overvoltage, molecular hydrogen is liberated in great quantities at the cathode so as to retard the desired electrolytic reduction.

During electrolysis, the acidic solution being electrolyzed is maintained at a temperature between about 1 C. and about 40 (3., preferably between the more restricted temperature range of 20 C. and 25 C. At temperatures much higher than 40 C., the amino acetophenone or other aminophenyl ketone is largely reduced to an alcohol rather than being reduced bimolecularly to the desired pinacol. .Attemperatures greatly below 15 C., current transmission and solubility diff culties may be encountered. During the course of electrolytic bimolecular reduction, the current density varies considerably, and it has been "found that the constant overvoltage impressed upon the cell forms a reliable means of controlling the pinacol formation.

In carrying out the electrolytic bimolecular reduction of paraarninoacetophenone, or other compounds containing the" aminophenyl ketone group, to produce the corresponding pinacols, the selected keto compound is first dissolved in a solution of a conductive acids'uch as hydrochloric acid, diluted with Water. Generally, the keto compound is dissolved to make a solution containing on a molar basis, .from one-half to one and one-half mols.'per .literand preferably about one mol. per liter. The aciolfsuch as for eX- an1ple,'hydrochloric' acid, is diluted to make a 5 bar is filled with the acidic solution of amino acetophenone or other aminophenyl ketones. The electrolytic cell Iis"provided with a mercury cathode and preferably a platinum anode and is further provided with heating and cooling means to maintain'the temperaturea't about 15 C. to 40 C. The electrolytic celllis also provided with means 'for maintaining a substantially constant overvoltage of, for example, 1.2 to 2 volts. The electrolysis is begun and continues until the electrolytic reduction is terminated; as is usually indicated by strong hydrogen evolution at the mercury cathode. After completion of the reduction, the catholyte containing the desired pinacol is treated to remove excess water and hydrochlo ric acid, as by evaporation to dryness, and then extracted with anhydrous ethanol containing ethyl acetate for the purpose of removing byproducts and unconverted raw material. The

purified residue, namely the hydrochloride '01" other acid saltof the desired pinacol, is then dissolved in water and'made'slightly alkaline with caustic soda, ammonia, or other alkali'to liberate the. free base. Upon treatment with alkali, a pre- 'cipitate is formed which is filtered off, washed with water andrecrystallized from acetone, ethylfor heating and coolingthe same.

ene glycol monoethyl ether, or other suitable sol- EXAMPLE I Preparation of (para-aminophenyl) methyl ethylene glycol dihydrochlorzde and its free base Six grains of para-aminoacetophenone are dissolved in 300 cc. of 5% hydrochloric acid and placed in the mercury cathode chamber of a diaphragm-type electrolytic cell provided with means The compartments are separated into an anode chamber and a cathode chamber by a permeable diaphragm whichiri this example was a regenerated cellulose foil sold to the trade as Visking sausage skin. The anode chambercontains a platinum anode and a 5% solution of hydrochloric acid. The current is startedand the electrolytic reduction proceeds at an overvoltage of 1.2 volts. Theinitial applied voltage is 4.6 volts andthe initial current flowing through the cell is 1.5 amperes. After about one hour, the contents of the cathode chamber are removedand evaporated to dryness under vacuum at room temperature whereby hydrochloric acid and water are removed. The residue remaining is triturated with about 25 to .30 ml. of anhydrous ethanol. To this is then added an equal amount of ethyl acetate, the resulting mixture is chilled and the undissolved portion filtered off. The resulting residue is then again washed with a cold mixture of equal parts anhydrous ethanol and ethyl acetate. .After drying, a yield of. bis-(p'a-raeaminophenyl) methyl ethyl ene glycol dihydrochloride in an amount of 18% of the theoretically possible yieldis obtained. The product was a light yellow powder, decomposing at about 230 C. .By combiningthe wash liquids employed above with the mother-liquor and evaporating to dryness, a byproduct identified as alpha-para-aminophenyl ethanol hydrochloride may be obtained. The free base, bis-(paraaminop-henyl) methyl ethylene. glycol, is prepared by dissolving the dihydrochloride in water, adding suificient sodium hydroxide tomato the solution slightly alkaline, whereby aprecipitate is formed, filtering ed the precipitate and washin the same with water 'to'remove the sodium chloride formed. The precipitate is recrystallizedfrom acetone to produce bis-(par.a=-aminophenyl) methyl ethylene glycol having a melting point of 248-249" C., in the form of white platelets, V 5

EXAMPLE II Eighty-one grams of paraeaminoacetophenone is dissolved in 600 ml; of 13.5% hydrochloric acid and subjected to electrolytic bimolecular reduction in thee1ectrolytic cell described inExample I at an overvoltage of 1.5 volts-while maintaining the catholyte temperature within the range of 20 C. to 30 C. The cell is provided with means for maintainin a constant overvoltage and the initial applied voltage is 4.5 volts yielding an initial cell current of- 3.2 amperes; After abcutsix hours, the completion of "the reduction is evidenced by the copious evolution of hydrogen from the mercury cathode surface and the catholyte containing th desired product is evaporated to dryness under vacuum at room temperature, extracted with anhydrous-ethanol 'and ethyl-ace tate as describedin Example-T, andpurified me,

manner similar to that described in Example I. Bis-(para-aminophenyl) methyl ethylene glycol dihydrochloride is recovered in a yield that is 65 of that theoretically possible.

By neutralizing a solution of the hydrochloride above prepared and recrystallizing from ethyl Cellosolve (the mono-ethyl ether of ethylene glycol) bis- (para-aminophenyl) methyl ethylene glycol having a melting point of 248249 C. is recovered in the form of white platelets.

From the foregoing, it will be apparent that this invention provides a simple process for the electrolytic bimolecular reduction of para-aminoacetophenone or other aminophenyl ketones to form the corresponding alpha beta disubstituted pinacols. Yields of 65% of the theoretical have been obtained. The new pinacols produced have antiestrogenic properties and are themselves useful as intermediates in the production of compounds having estrogenic activity.

Various changes may be made in the invention without departing from the spirit and scope thereof.

What is claimed is:

1. In a. process for the production of alpha, beta substituted bis-(aminophenyl) ethylene glycols the step which comprises subjecting an acidic solution of a compound containing the aminophenyl ketone nucleus to electrolytic reduction at a substantially constant cathode overvoltage above the decomposition potential of the compound being reduced but below the overvoltage at which substantial quantities of molecular hydrogen are liberated.

2. The process of claim 1 wherein the overvoltage is maintained between 1.2 and 2.0 volts.

3. In a process for the production of a bis- (para-aminophenyl) methyl ethylene glycol the step which comprises subjecting an approximately one molar solution of para-aminoacetophenone in hydrochloric acid to electrolytic bimolecular reduction at a temperature between 15 C. and C. and at a substantially constant cathode overvoltage between 1.2 to 1.6 volts.

4. In a process for the production of bis-(paraaminophenyl) methyl ethylene glycol the step which comprises subjecting a para-amino-acetophenone solution of one molar concentration in 13.5% hydrochloric acid to electrolysis at a substantially constant cathode overvoltage of about 1.5 volts, and an initial applied voltage of about 4.5 volts, while employing a cellophane-shrouded platinum anode, a mercury cathode and maintaining the electrolyte temperature at 20 C.-25 0., and continuing said electrolysis until bis- (para-aminophenyl)methyl ethylene glycol hydrochloride is formed.

MILTCN J. ALLEN.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Number Name Date 2,393,156 Gibbs Jan. 15, 1946 2,393,930 Parker et al Jan. 29, 1946 2,408,036 Boettger et a1 Sept. 24, 1946 2,408,101 Slotterbeck Sept. 24, 1946 2,422,468 Chambers et al June 17, 1947 OTHER REFERENCES Hickling: Transactions Faraday Society, vol. 38 (1942) pages 27-33.

Glasstone et al.: Electrolytic Oxidation and Reduction, (1936), pages 183-185.

Hibbert et al.: Journal American Chemical Society, vol. 46 (April 1924), pages 983-999. 

1. IN A PROCESS FOR THE PRODUCTION OF ALPHA, BETA SUBSTITUTED BIS-(AMINOPHENYL) ETHYLENE GLYCOLS THE STEP WHICH COMPRISES SUBJECTING AN ACIDIC SOLUTION OF A COMPOUND CONTAINING THE AMINOPHENYL KETONE NUCLEUS TO ELECTROLYTIC REDUCTION AT A SUBSTANTIALLY CONSTANT CATHODE OVERVOLTAGE ABOVE THE DECOMPOSITION POTENTIAL OF THE COMPOUND BEING REDUCED BUT BELOW THE OVERVOLTAGE AT WHICH SUBSTANTIAL QUANTITIES OF MOLECULAR HYDROGEN ARE LIBERATED. 